Processes for the preparation of Glasdegib and salt thereof and solid state forms of Glasdegib maleate and process for preparation thereof
The present disclosure relates to safe and efficient processes for the synthesis of Glasdegib or salts thereof, preferably Glasdegib Maleate. The present disclosure also encompasses solid state forms of Glasdegib maleate, in embodiments crystalline polymorphs of Glasdegib maleate, processes for preparation thereof, and pharmaceutical compositions thereof.
1 . A crystalline form of Glasdegib Maleate characterized by data selected from one or more of the following:
a) an XRPD pattern having peaks at 7.0, 10.6, 14.1, 24.2 and 25.5 degrees 2-theta±0.2 degrees 2-theta;
b) an XRPD pattern as depicted in FIG. 1 ;
c) a solid state 13 C NMR spectrum having peaks at 101.9, 113.1, 116.9, 131.5, 136.2 and 149.5 ppm±0.2 ppm;
d) a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a reference peak at 57.3 ppm±2 ppm of 44.6, 55.8, 59.6, 74.2, 78.9 and 92.2 ppm±0.1 ppm;
e) a solid-state 13 C NMR spectrum substantially as depicted in FIG. 8 a , 8 b or 8 c ; and
f) combinations of two or more of: a, b, c, d, and e.
2 . The crystalline form of Glasdegib Maleate according to claim 1 , which is characterized by an XRPD pattern having peaks at 7.0, 10.6, 14.1, 24.2 and 25.5 degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three, four, or five additional peaks selected from 11.3, 11.8, 13.3, 15.9, and 26.2 degrees two theta±0.2 degrees two theta.
3 . The crystalline form of Glasdegib Maleate according to claim 1 , which is characterized by an XRPD pattern having peaks at 7.0, 10.6, 11.3, 11.8, 13.3, 14.1, 15.9, 24.2, 25.5, 26.2 degrees 2-theta±0.2 degrees 2-theta.
4 . The crystalline form of Glasdegib Maleate according to claim 1 , wherein said crystalline form is an acetic acid solvate.
5 . The crystalline form of Glasdegib Maleate according to claim 1 , which contains no more than about 20% of any other crystalline forms of Glasdegib Maleate.
6 . The crystalline form Glasdegib Maleate according to claim 1 , which contains no more than about 20% of amorphous Glasdegib Maleate.
7 . A pharmaceutical composition comprising the crystalline form of Glasdegib Maleate according to claim 1 .
8 . A pharmaceutical formulation comprising the crystalline form of Glasdegib Maleate according to claim 1 , with at least one pharmaceutically acceptable excipient.
9 . A process for preparing a pharmaceutical formulation comprising combining the crystalline form of Glasdegib Maleate according to claim 1 with at least one pharmaceutically acceptable excipient.
10 . A method of treating acute myeloid leukemia, comprising administering a therapeutically effective amount of the crystalline form of Glasdegib Maleate according to claim 1 , to a subject in need of the treatment.